tbuckley/cabot-search huggingface dataset:
ANGI-10. METRONOMIC 5 DRUG ANTI-ANGIOGENESIS THERAPY FOR RECURRENT EPENDYMOMA
Authors: Braden Olsen, Ossama Maher, Toba Niazi, John Ragheb, Ziad Khatib
Journal: Neuro-Oncology (2023)

Abstract Low dose continuous (metronomic) anti-angiogenesis therapy is a treatment regimen currently under investigation for chemo-refractory tumors to target tumor vasculature. This effect has been shown to improve survival in primary brain tumors such as medulloblastoma. The Dana Farber Antiangiogenic Chemotherapy Phase II Trial and MEMMAT trial are investigations into outcomes of metronomic anti-angiogenesis therapy for children with recurrent ependymoma, among other primary brain tumors. We retrospectively report 9 pediatric patients diagnosed between the ages of 1 and 8 with surgery and radiation refractory posterior fossa ependymoma that were treated with 5 drug metronomic anti-angiogenesis therapy including celecoxib, thalidomide, fenofibrate, and alternating low dose etoposide and cyclophosphamide. For one patient, we added bevacizumab every other week. 7 patients had anaplastic presentation of ependymoma. All patients either had gross total resection or multiple subtotal resections. Tumor markers include GFAP, S100, EMA, OLIG 2, CD99, and Ki-67. Side effects were primarily hematologic but also included muscle pain, constipation, and dizziness, however treatment was tolerated well overall. The primary reason for stopping treatment early was progression of disease, no patients stopped therapy for side effects. There was no change in response to therapy based on tumor markers found. 2-year survival was 78% and 2-year progression free survival was 56%. 3/9 patients have no recurrent disease, two of these patients had anaplastic ependymoma and 1 presented with metastatic disease to the spine. We show improved outcomes with a minimal side effect profile for metronomic anti-angiogenesis therapy in pediatric patients with recurrent ependymoma refractory to surgical and radiation therapy.
SURG-37. ONCOGENIC MUTATIONS AND TUMOR CHARACTERISTICS IN OLFACTORY GROOVE MENINGIOMAS: IMPLICATIONS FOR PERSONALIZED TREATMENT STRATEGIES
Authors: Insa Prilop, Friederike Beyer, Sylvia Herold, Majd Alkhatib, Daniel Cahill, Hiroaki Wakimoto, Priscilla Brastianos, Ilker Eyuepoglu, Gabriele Schackert, Tareq Juratli
Journal: Neuro-Oncology (2023)

Abstract OBJECTIVE To investigate the correlation between clinical and radiologic features of olfactory groove meningiomas (OGM) and their tumor molecular profiles, focusing on oncogenic mutations identified through genomic studies. METHODS Targeted next-generation sequencing analyses were conducted on 54 patients with OGM (37 females and 17 males) to determine the frequency of SMO, AKT1, PIK3CA, and other mutations. The molecular results were then correlated with clinical and radiographic tumor features. RESULTS Among the OGM patients, SMO mutations were found in 16 (29.6%) cases, AKT1 mutations in 13 (24.1%), and PIK3CA/PIK3R1 mutations in 9 (16.7%) cases. Less common mutations in POLR2A, SUFU, and NF1 were observed in 8 (14.8%) cases, while 8 OGM (14.8%) did not have identifiable driver mutations (Wild-type group, WT). The median age at first diagnosis was 64.1 years (25-87 years), with the youngest group represented by PIK3CA-mutant patients at 52 years (49-78 years). The sex distribution was similar across the SMO-, AKT1- and PIK3CA-mutant groups (F:M = 2.1:1). OGM with SMO mutations exhibited larger tumor volumes (329.4 ± 323.0 cm3) compared to AKT1-mutant tumors (283.3 ± 156.2 cm3). Tumor infiltration of the ethmoid cells was found in 10 cases (22.2%), with the highest rate observed in PIK3CA-mutant OGM (40%), followed by 25% in SMO-mutant OGM. Tumor-associated hyperostosis of the sphenoid planum was common in OGM (72.2%), with the highest rate in the SMO group (75.0%) and the lowest rate in the AKT1-mutant group (30.8%). The majority of cases (n = 45, 83.3%) were classified as WHO grade 1 meningioma, while the remaining nine cases were WHO grade 2 (n = 8) and 3 (n = 1). CONCLUSIONS Overall, our data demonstrate the presence of clinically actionable mutations in the majority of olfactory groove meningiomas, and suggest a correlation between molecular status and common clinical and radiologic tumor features.
SURG-40. AWAKE CRANIOTOMY IN A MIDDLE-INCOME COUNTRY. CHALLENGES AND TECHNICAL NUANCES
Authors: Alvino De Leon, Eduardo Wong, Maria Antonia Villarreal
Journal: Neuro-Oncology (2023)

Abstract OBJECTIVES Describe the first experience in this technically challenging procedure RESULTS on morbidity INTRODUCTION Awake craniotomy allows for maximal safe resection and lower incidence of adverse events. Nonetheless, it represents a technical challenge. METHODS We enroll forty patients, 18 women, and 22 men. Due to the lack of a navigation system, craniometrics points became paramount to craniotomy planning. Ultrasound is used to compensate for brain shift and confirm the tumor's exact location. We engaged in cortical and subcortical mapping and clinical evaluation of motor and sensory functions. Linguistic tests were applied. The first 24 hours are in the ICU, and an MRI is obtained. RESULTS The mean age was 51, and the mean Karfnosky scale was 80. The median size was 12 cm3. Locations were: Thirteen precentral gyri. Ten insular cortex. Eight cingulate gyri. Six supplementary motor gyri Two Supramarginal gyri. One paracentral lobe tumor. Four patients had obese morbidity, three had depression, and two had a midline displacement treated with steroids. Intraoperative, we encountered three seizures managed with cold saline, two speech arrest, and one transient hand motor deficit. Post-op adverse events were one central facial paralysis, one upper limb, and one lower limb paresthesias; all improved after 72 hours. The median length of stay is 48 hours. The median extent of resection is 93%. The mean KPS was 80 at discharge. We undertook a median of 18 months follow-up. 38 Glioblastomas(GMB) and 2 Low-Grade Gliomas(LGG) were found. The standard oncology treatment was Temozolomide and stereotaxic radiosurgery(SRS). The median time from surgery to SRS was 4.3 months. The median SRS marginal and maximal dose were 15Gy and 26Gy. The median overall survival(OS) was sixteen months, and the Progression-free survival(PFS) was ten months. CONCLUSION An awake craniotomy without the navigation system is possible; however, careful planning is essential.
SURG-02. SURGICAL OUTCOME OF SUPRATENTORIAL MENINGIOMA PATIENTS AGED ≥80 YEARS – RETROSPECTIVE INTERNATIONAL MULTICENTER STUDY
Authors: Christoph Schwartz, Ilari Rautalin, Jürgen Grauvogel, Marco Bissolo, Waseem Masalha, Christine Steiert, Oliver Schnell, Juergen Beck, Florian Ebel, David Bervini, Andreas Raabe, Thomas Eibl, Hans-Herbert Steiner, Nathan A Shlobin, Khizar R Nandoliya, Mark W Youngblood, James P Chandler, Stephen Magill, Alexander Romagna, Jens Lehmberg, Manuel Fuetsch, Julian Spears, Arwin Rezai, Barbara Ladisich, Matthias Demetz, Christoph J Griessenauer, Mika Niemelä, Miikka Korja
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Demographic changes will lead to an increase in old patients, a population with significant risk of postoperative morbidity and mortality, requiring neurosurgery for meningiomas, Objective: To evaluate outcome of supratentorial meningioma patients aged ≥80 years. This multicenter study aims to report neurofunctional status after resection, to identify factors associated with outcome, and to validate a previously proposed decision support tool. METHODS Neurofunctional status was assessed by the Karnofsky Performance Scale (KPS). Patients were categorized in poor (KPS ≤40), intermediate (KPS 50-70), and good (KPS ≥80) preoperative subgroups. Volumetric analyses of tumor and peritumoral brain edema (PTBE) were performed; volumes were scored as small (&amp;lt; 10 cm3), medium (10-50 cm3), and large ( &amp;gt;50 cm3). RESULTS The study population consisted of 262 patients. Median age at surgery was 83.0 years. Median preoperative KPS was 70; 117 (44.7%) patients were allotted to the good, 113 (43.1%) to the intermediate, and 32 (12.2%) to the poor subgroup. Median tumor and PTBE volumes were 30.2 cm3 and 27.3 cm3; large PTBE volume correlated with poor preoperative KPS status (P = .008). The 90-day and 1-year mortality rates were 9.0% and 13.2%. Within the first postoperative year, 101 (38.5%) patients improved, 87 (33.2%) were unchanged, and 74 (28.2%) were functionally worse (including deaths). Each year-increase of age associated with 44% (23–70%) increased risk of 90-day and 1-year mortality. In total, 111 (42.4%) patients suffered from surgery-associated complications. Maximum tumor diameter ≥5cm (odds ratio 1.87 (1.12–3.13)) and large tumor volume (odds ratio 2.35 (1.01–5.50)) associated with an increased risk of complications. Among patients with poor preoperative status and large PTBE, most (58.3%) benefited from surgery. CONCLUSION Patients with poor preoperative status and large PTBE most often showed postoperative improvements. The decision support tool may be of help in identifying cases that most likely benefit from surgery.
RBIO-09. HMGB2 INHIBITION RADIO-SENSITIZES GLIOBLASTOMA CELLS INDEPENDENTLY OF THEIR TP53-MUTATION STATUS
Authors: Aline Becker, Valesio Becker, Ebin Sebastian, Christian Showalter, Joseph McElroy, S Jaharul Haque, Arnab Chakravarti
Journal: Neuro-Oncology (2023)

Abstract Alterations in TP53 are major drivers of radiation resistance in gliomas. High Mobility Group Box 2 (HMGB2) has been implicated in resistance to temozolomide through p53-phosphorylation during DNA double-strand break repair and in silico analysis suggests its involvement in the p53-p21-RB signaling pathway. Nevertheless, the role of HMGB2 in radiation response has not been fully explored in gliomas. While HMGB2 is virtually not expressed in the normal adult brain, increasing expression with histopathological glioma grade correlates with poor patient survival. We confirmed increased HMGB2 expression in grade 3 compared to grade 2 gliomas using ClariomD and observed spatial heterogeneous HMGB2 expression in glioblastomas (GBMs) in histopathology-targeted supervised proteomic analysis employing liquid chromatography tandem mass spectroscopy (LC-MS-MS). Here, we aimed to study HMGB2 effects in cell proliferation and response to radiation in a set of molecularly distinct genetically engineered GBM cell lines (IDHwt). Using an established U87 GBM cell line and isogenic primary GBM cell lines GBM3359 TP53wt and CRISPR/Cas9-engineered mutant TP53 (R248W) generated in our laboratory, we successfully produced clones with either HMGB2 shRNA knockdown (KD – over 70% reduction) or HMGB2 lentiviral-mediated overexpression (OE – 3-76x higher expression). HMGB2-KD reduced cell proliferation (10% in U87; 20-25% in isogenic GBM3359 cell lines) and colony formation (more than 50% reduction), which was further rescued with HMGB2 OE in all cell lines. Half maximal inhibitory concentration (IC50) for radiation was determined by methylene blue cell proliferation and clonogenic assays, which showed that HMGB2-KD decreased the IC50 while rescued HMGB2 OE increased RT resistance of all clones. Taken together, our data suggest that HMGB2 inhibition may improve radiation response independently of TP53 status in gliomas. Further mechanistic studies to elucidate the relationship between HMGB2 and TP53 are underway to unfold the contribution of heightened HMGB2 expression to radiation resistance mechanisms in gliomas.
CTIM-01. NIVOLUMAB AND STEREOTACTIC RADIOSURGERY (SRS) FOR PATIENTS WITH BREAST CANCER BRAIN METASTASES: LONG TERM RESULTS AND CELL FREE DNA (CFDNA) ASSESSMENT FROM A NON-RANDOMIZED, OPEN-LABEL, PHASE IB STUDY
Authors: Kamran Ahmed, Youngchul Kim, John Arrington, Sungjune Kim, Michelle DeJesus, Aixa Soyano, Avan Armaghani, Ricardo Costa, Hung Khong, Loretta Loftus, Marilin Rosa, Jimmy Caudell, Roberto Diaz, Arnold Etame, Nam Tran, Hatem Soliman, Brian Czerniecki, Peter Forsyth, Hsiang-Hsuan Michael Yu, Hyo Han
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND We hypothesized treatment with nivolumab and SRS would be feasible and well tolerated and may improve intracranial tumor control over SRS alone for breast cancer brain metastases. METHODS The study is a phase Ib trial of nivolumab and SRS for breast cancer brain metastases. Clinical trial information: NCT03807765. Key eligibility criteria include breast cancer brain metastases of all subtypes, age ≥ 18, ECOG ≤ 2 with ≥ 10 brain metastases. Treatment was initiated with a dose of nivolumab (480 mg IV) that was repeated every 4 weeks. The initial dose of nivolumab was followed 1 week later by SRS. Blood was collected at baseline and q4 weeks. RESULTS A total of 12 patients were treated to 17 brain metastases. Breast cancer subtypes included triple negative (50%), HR+/HER2- (33%), and HR-/HER2+ (17%). Median follow-up from start of protocol therapy is 44 months. Two lesions were noted to undergo local failure, both pathologically confirmed, for a 12-month local control of 94%. Median distant intracranial control was 7.4 months with a 12 month control rate of 33%. Median systemic progression free survival was 7.7 months with a 12 month rate of 42%. Median overall survival (OS) was 24.7 months with a 12 month OS of 75%. No cases of radionecrosis were noted. Most patients were noted to have an increase in cfDNA throughout study treatment, at week 5 compared to baseline (83%), week 25 compared to baseline (89%), and 100% at first follow-up. An increase in cfDNA 4 weeks post SRS was found to predict worse intracranial control (HR: 4.4; 95% CI: 1.1-18.5; p = 0.04). CONCLUSIONS Nivolumab and SRS is a safe and feasible treatment option in breast cancer brain metastases. An increase in cfDNA 4 weeks post SRS was found to predict worse intracranial control and was eventually seen in all patients.
IMMU-18. ESTABLISHMENT OF CAR-NK CELL THERAPY TARGETING B7-H3 AGAINST GLIOBLASTOMA
Authors: Tetsuro Tachi, Noriyuki Kijima, Hideki Kuroda, Shunya Ikeda, Koki Murakami, Ryuichi Hirayama, Yoshiko Okita, Naoki Kagawa, Naoki Hosen, Haruhiko Kishima
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) has a poor prognosis despite intensive treatment by surgery, radiation, and chemotherapy, thus new therapeutic strategies are urgently needed. Recently, CAR (chimeric antigen receptors) -T cell therapy, which uses genetically engineered T cells to express CAR has been extensively investigated. However, although CAR-T cell therapy has shown some efficacies in preclinical GBM models, it exhibited limited efficacy and undesirable side effects such as graft-versus-host disease when adapted for clinical trials. In contrast, cord blood-derived natural killer (NK) cells show a robust safety profile in preclinical models and CAR-NK cell therapy is an attractive therapeutic option for cancer treatment. In this study, we aim to analyze the therapeutic efficacy of CAR-NK therapy against GBM. We used B7-H3 as a target antigen for CAR-NK cell therapy because B7-H3 has recently been reported to be a tumor specific antigen for GBM. First, we generated CAR-T cells expressing CAR targeting B7-H3. We found that CAR-T cells targeting B7-H3 produced IL-2 and IFNɤ and exerted cytotoxicity to GBM cells by chromium 51 release assay. In addition, in an orthotopic mouse model, CAR-T cells targeting B7-H3 showed survival benefits compared with control CAR-T cells. Next, we generated CAR-NK cells targeting B7-H3 from cord blood-derived NK cells and found robust cytolytic activity against GBM cells in vitro. These results suggest that cord blood-derived CAR-NK cells targeting B7-H3 may be a promising therapy for GBM and further studies are necessary to examine whether cord blood-derived CAR-NK cells targeting B7-H3 could be a therapeutic strategy against GBM.
TMIC-46. SINGLE-CELL MAPPING OF HUMAN BREAST CANCER BRAIN METASTASES REVEALS PROGNOSTICALLY RELEVANT IMMUNE LANDSCAPES
Authors: Lena Jassowicz, John Wong, Julia Soller, Furkan Sor, Fangyoumin Feng, Mandy Barthel, Andreas Unterberg, Peter Lichter, Rolf Warta, Marc Zapatka, Martina Seiffert, Christel Herold-Mende
Journal: Neuro-Oncology (2023)

Abstract Brain metastases are associated with a particularly poor prognosis in breast cancer and improved treatment strategies are much needed. The patient-individual role of immunotherapy and anti-tumor immune control in breast cancer brain metastases (BCBM) is still poorly understood. Here, we characterized the niche-specific tumor microenvironment of BCBM at single-cell resolution in a clinically annotated patient cohort that underwent surgery at Heidelberg University Hospital (n = 156). Quantification of T cell infiltrates across whole tissue sections of n = 137 BCBM revealed strong inter-patient heterogeneity of T cell abundance. Of note, high CD8 T cell densities predicted prolonged overall survival independent of established prognostic factors. Deeper phenotyping of BCBM T cells and matched blood samples by flow cytometry showed a specific enrichment of a CD103+ tissue resident-like CD8 T cell subset expressing high levels of activation markers and checkpoint molecules in BCBM. In contrast to a general T cell enrichment in the stroma, this subset was detected more frequently within tumor islands, which might suggest its anti-tumor reactivity. We investigated potential regulators of T cell infiltration and function in the brain metastatic niche focusing on the triple negative breast cancer sub-cohort (n = 49) concluding the following: i) The quantification of a broad range of immune cells, incl. myeloid cells, NK, and B cells, in whole tissue sections revealed distinct immune ecotypes associated with T cell infiltrates. ii) An in-depth characterization of all major immune and stromal cells by single nuclei RNA-sequencing (n = 28/49) allowed for identification of potential cellular and molecular interaction partners, which was confirmed by iii) analysis of their neighborhoods by spatial transcriptomics in a targeted, single-cell resolving approach (n = 8/28). We anticipate that our findings will reveal immunoregulatory cell subsets and molecules and potentially contribute to improving immunotherapeutic approaches for BCBM patients in the future.
QOL-08. LONGITUDINAL EFFECTS OF A PSYCHOLOGICAL INTERVENTION FOR CAREGIVERS OF PATIENTS WITH PRIMARY MALIGNANT BRAIN TUMORS: SECONDARY ANALYSIS OF A RANDOMIZED CONTROLLED TRIAL
Authors: Sumita Strander, Alyx Podgurski, Shibani Datta, Kedie Pintro, Nora Horick, Joseph Greer, Lara Traeger, Areej El-Jawahri, Timothy Sannes, Jennifer Temel, Jamie Jacobs, Deborah Forst
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Caregivers of patients with primary malignant brain tumors (PMBT) experience high rates of anxiety. In our randomized controlled trial assessing the effects of a caregiver-directed, telehealth-based psychological intervention (“NeuroCARE”), NeuroCARE participants had significantly lower anxiety symptoms (primary outcome) and depression symptoms, and better self-efficacy and coping immediately post-intervention compared to usual care (UC). We subsequently examined the longitudinal effects of NeuroCARE on caregiver-reported outcomes across all study timepoints. METHODS We enrolled and randomized 120 caregivers of patients with PMBT to NeuroCARE (N = 60) versus usual supportive care (N = 60). Eligible participants had significant baseline anxiety symptoms (Generalized Anxiety Disorder-7 score ≥ 5). We collected caregiver-reported anxiety symptoms (Hospital Anxiety and Depression Scale (HADS)–Anxiety Subscale), depression symptoms (HADS–Depression Subscale), self-efficacy (Lewis Cancer Self-Efficacy scale), coping (Measure of Current Status), quality of life (QOL; CareGiver Oncology Quality of Life survey), caregiver burden (Caregiver Reaction Assessment) and post-traumatic stress disorder (PTSD) symptoms (PTSD Checklist for DSM-5) at baseline, 11 weeks (immediately post-intervention) and 16 weeks (one-month post-intervention). We used mixed effects linear regression models to assess longitudinal intervention effects on study outcomes. RESULTS Enrolled caregivers had a mean age of 53 years; the majority were female (99/120; 82.5%) and were the patient’s spouse/partner (84/120; 70%). NeuroCARE participants experienced greater improvement than UC in depression symptoms (change/week [slope]: -0.09 vs. -0.01, p = 0.041), self-efficacy (slope: 0.64 vs. -0.17, p = 0.006) and coping (slope: 0.31 vs. -0.01, p &amp;lt; 0.001). We observed non-statistically significant differences between NeuroCARE and UC for change in anxiety symptoms (slope: -0.13 vs. -0.05, p = 0.059) and QOL (slope: 0.26 vs. 0.04, p = 0.050). Study arms did not differ in longitudinal trajectories for caregiver burden or PTSD symptoms. CONCLUSIONS NeuroCARE participants experienced greater improvements over time in depression symptoms, self-efficacy, and coping than UC participants, highlighting the sustained benefits of this caregiver-directed supportive intervention.
BIOM-27. CELL-FREE DNA-BASED LIQUID BIOPSIES FOR THE REAL-TIME TRACKING OF TUMOR BURDEN AND TREATMENT RESPONSE IN GLIOBLASTOMA
Authors: Sharvari Mankame, Maria Kyriakidou, Nanyun Tang, George Reid, Michael Berens, Christine Brown, Jana Portnow, Floris Barthel
Journal: Neuro-Oncology (2023)

Abstract Cell-free DNA (cfDNA) are short fragments of DNA that are released by apoptotic or necrotic cells into bodily fluids. It has emerged as a potential diagnostic tool allowing for the detection and analysis of tumor-derived biomarkers in cancer. Despite the detailed view provided by clinical imaging, its inability to quantify tumor burden and distinguish between pseudo-progression and pseudo-response poses a challenge for patients. In this study, we sought to investigate the effectiveness of cfDNA as a liquid biopsy tool to track tumor burden and disease progression in real time in different glioblastoma models and through different types of biofluids. To examine the feasibility of cfDNA-based tumor tracking we cultivated several patient-derived glioblastoma lines, purified cfDNA and performed sequencing. Further analysis revealed that dead cells were associated with an elevated cfDNA yield and altered fragment size profiles. Genomic sequencing revealed consistent variants shared across serial cfDNA timepoints, strengthening the suggestion that cfDNA can be used as a non-invasive biomarker. In order to demonstrate the clinical implications of our methodology, we collected a preliminary batch of n = 43 longitudinal intraventricular cerebrospinal fluid (CSF) samples from a patient that underwent CAR-T treatment over the span of two years. We observed a marked increase in cfDNA yield post-treatment compared to samples taken prior to treatment administration. Furthermore, cfDNA-based estimates of tumor burden measured as allele fraction specific to the tumor, tracked with clinical imaging-based tumor size estimates. These preliminary findings provide compelling evidence supporting the clinical utility of cfDNA analysis in monitoring the effectiveness and dynamics of CAR-T treatment. By tracking cfDNA levels in CSF, we can identify patterns reflecting treatment response and aid in assessing the therapeutic efficiency of CAR-T treatment in glioma patients. Further investigations with larger patient cohorts and more comprehensive data analysis to validate these findings are actively underway.